Early studies focused on septic shock pathophysiology (Am J Physiol, 1988; Chest, 1990), the role of endotoxemia (J Clin Invest, 1989; J Exp Med, 1989; Chest. 1991; N Engl J Med, 1993; Infect Immun. 1996), and the efficacy of various anti-endotoxin therapies (Antimicrob Agents Chemother. 1989) including lipid A analogs (J Clin Invest. 1987; Pharm Res. 1990) and antibodies (JAMA, 1993; J Infect Dis, 1994). Nitric oxide was examined as an important mediator of septic shock (Crit Care Med, 1993; JAMA, 1996). Non-selective nitric oxide synthase inhibitors were found to be sometimes toxic and never beneficial (J Exp Med, 1992; Crit Care Med, 1998; Am J Respir Crit Care Med, 1998). Normal volunteers challenged with endotoxin were shown to release increased amounts of nitric oxide. Although ibuprofen blocked endotoxin-induced increases in nitric oxide production, blood pressure was unaffected, suggesting that other mechanisms compensated to maintain vasodilation (J Pharmacol Exp Ther. 1999). Severity of illness (risk of death) was found to influence the therapeutic efficacy of anti-inflammatory agents in septic shock (Am J Respir Crit Care Med, 2002). This finding was used by the FDA to re-analyze the PROWESS trial of rhAPC (Xigris) and led to initial approval only for patients with a high risk of death. The lack of rhAPC efficacy in patients with a low risk of death was confirmed in the ADDRESS trial. The administration of L-arginine without or with N-acetylcysteine in a canine model of septic shock was found to be harmful (Crit Care Med, 2006). L-arginine is a common component of immunonutrition formulas that are marketed for use in critically ill patients. Intra-aortic balloon counterpulsation was demonstrated to prolong survival in a hypodynamic canine model of Staphylococcus aureas pneumonia induced septic shock (Crit Care Med, 2009). This result suggests that counterpulsation support of left ventricular function might improve survival in episodes of septic shock associated with compromised cardiac output. A low cardiac output is seen in 10 to 20 percent of adults and up to 50 percent of children with septic shock. Anthrax lethal toxin (LT)-induced shock was found to differ substantially from LPS challenge in that fluids and vasopressors, standard approaches to septic shock, were harmful. Notably, anthrax infection fails to induce nitric oxide synthase 2, due to a LT-mediated truncation of inflammatory signaling inside cells. Interactions between LT and nitric oxide are being examined to determine the therapeutic potential of nitric oxide-based treatment strategies (manuscript in preparation, 2009). An investigation of the hypothalamic-pituitary-adrenal axis and potential benefits of glucocorticoids and mineralocorticoids is ongoing in mouse and canine models of septic shock. These experiments are aimed at defining issues of dose and timing as well as glucocorticoid and mineralicorticoid effects at the cellular level. The more general topic of nuclear receptor transrepression of inflammatory responses to sepsis is being explored both in vitro and in vivo. Staphylococcus enterotoxin B (SEB) can trigger a lethal super antigen-mediated cytokine storm that may contribute to the high mortality of S. aureas sepsis and also poses a threat as a potential bioweapon. Using an aerosolized-toxin, mouse model, the genome-wide effects of SEB are being examined in an effort to identify therapeutic targets.